Angiogenesis, the development of new capillaries from preexisting blood vessels, is a critical process in the progression of solid neoplasms and in many other pathological conditions such as diabetic retinopathy and rheumatoid arthritis (Folkman, J., Nature Medicine 1995, 1: 27–31). Different strategies to target the vascular development have been extensively studied and the availability of reliable in vitro model systems in model systems in angiogenesis research has been crucial for the study of specific inhibitors (Jain, R. K., et al., Nature Medicine 1997, 3: 1203–1208).
It is now widely recognized that the ability of a tumor to induce proliferation of new blood vessels from its host has a profound effect on cancer growth and metastasis. The process of tumor angiogenesis is mediated by a balance of positive and negative regulators of microvessel growth and the development of new blood vessels may be divided into three different sequential steps: 1) cell-mediated, proteolytic degradation of the basement membrane; 2) endothelial cell migration and proliferation out of the vessel into the surrounding extracellular matrix; 3) organization of the cells into tube-like structures (Folkman, J., Nature Medicine 1995, 1: 27–31).
Somatostatin (somatotropin release inhibiting factor or SRIF) has both a 14 amino acid isoform (somatostatin-14) and a 28 amino acid isoform (somatostatin-28). See Wilson, J. & Foster, D., Williams Textbook of Endocrinology, p. 510 (7th ed., 1985). The compound is an inhibitor of secretion of the growth hormone and was originally isolated from the hypothalamus. Brazeau, et al., Science 179:77 (1973). Native somatostatin has a very short duration of effect in vivo since it is rapidly inactivated by endo- and exopeptidase. Many novel analogs (e.g., peptide and non-peptide compounds) have been prepared in order to enhance the duration of effect, biological activity, and selectivity (e.g., for the particular somatostatin receptor) of this hormone. Such analogs of somatostatin will be called “somatostatin agonists” herein.
Various somatostatin receptors (SSTRs) have been isolated, e.g., SSTR-1, SSTR-2, SSTR-3, SSTR-4, and SSTR-5. Thus, a somatostatin agonist may be a SSTR-1 agonist, and/or a SSTR-2 agonist, and/or a SSTR-3 agonist, and/or a SSTR-4 agonist and/or a SSTR-5 agonist.
The antiangiogenic activity of somatostatin analogues has been previously demonstrated in some in vitro and in vivo experimental models (Danesi, R. et al., Clinical Cancer Research 1997, 3: 265–272; Woltering, E. A., et al., Investigational New Drug 1997, 15: 77–86). In addition to this, long-term octreotide treatment was able to reduce the progression of neovascularization associated with severe proliferative retinopathy in diabetic patients (Mallet et al., 1992).
The determination of which somatostatin subtype or subtypes are involved in the antiangiogenic property of somatostatin would allow for the development of therapeutic compositions with maximum efficacy and minimum side effects. However, previous studies in this field have resulted in contradictory and/or inconclusive findings regarding the role which each of the five somatostatin receptor subtypes may play in respect of the antiangiogenic activity of somatostatin.